Use of agonists of formyl peptide receptor 2 for treating dermatological diseases

ABSTRACT

The present invention relates to a method for treating dermal inflammation and dermal diseases by local or systemic delivery, in a subject in need of such treatment, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of Formyl peptide receptor 2 (FPR2).

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/566,682, filed Sep. 10, 2019, which is a continuation of U.S. patentapplication Ser. No. 15/490,127, filed Apr. 18, 2017, now U.S. Pat. No.10,434,112, which is a continuation of U.S. patent application Ser. No.14/196,155, filed Mar. 4, 2014, now abandoned, which claims the benefitof U.S. Provisional Patent Application Ser. No. 61/773,778 filed Mar. 6,2013, which are herein incorporated by reference in their entireties andserve as the basis of a priority and/or benefit claim for the presentapplication.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to a method for treating dermalinflammation and dermal diseases by local or systemic delivery, in asubject in need of such treatment, which comprises administering apharmaceutical composition comprising a therapeutically effective amountof at least one agonist of Formyl peptide receptor 2 (FPR2).

Summary of the Related Art

The formyl peptide receptor (FPR) family belongs to the seventransmembrane domain G-protein-coupled receptor (GPCR) family. Thisfamily includes 3 members in humans and one member of this family FPR2(also known as FPRL-1, ALXA4) is expressed predominantly on inflammatorycells such as monocytes and neutrophils, as well as on T cells and hasbeen shown to play a critical role in leukocyte trafficking duringinflammation and human pathology (Chiang N, Serhan C N, Dahlen, S,Drazen J M, Hay DWP, Rovati E, Shimizu T, Yokomizo T, Brink, C. Thelipoxin receptor ALX: Potent ligand-specific and stereoselective actionsin vivo. Pharmacological Reviews 2006; 58: 463-519). FPR2 is anexceptionally promiscuous receptor that responds to a menagerie ofstructurally diverse exogenous and endogenous ligands, including serumamyloid A (SAA), chemokine variant sCKβ8-1, the neuroprotective peptidehumanin, anti-inflammatory eicosanoid lipoxin A4 (LXA4) andglucocorticoid-modulated protein annexin A1 (Chiang N, Serhan C N,Dahlen, S, Drazen J M, Hay DWP, Rovati E, Shimizu T, Yokomizo T, Brink,C. The lipoxin receptor ALX: Potent ligand-specific and stereoselectiveactions in vivo. Pharmacological Reviews 2006; 58: 463-519). FPR2 hasbeen shown to transduce anti-inflammatory effects of arachidonic acidderived Lipoxin A4 (LXA4) in many systems, and has been shown to play akey role in the resolution of inflammation (Dufton N, Perretti M.Therapeutic anti-inflammatory potential of formyl peptide receptoragonists. Pharmacology & Therapeutics 2010; 127: 175-188). FPR2 knockoutmice show exaggerated inflammation in disease conditions as expected bythe biological role of the receptor (Dufton N, Hannon R, Brancaleone V,Dalli J, Patel H B, Gray M, D'Aquisto F, Buckingham J C, Perretti M,Flower R J. Anti-inflammatory role of the murine formyl-peptide receptor2: Ligand-specific effects on leukocyte responses and experimentalinflammation. Journal of Immunology 2010; 184: 2611-2619. Gavins FNE,Hughes E L, Buss NAPS, Holloway P M, Getting S J, Buckingham J C.Leukocyte recruitment in the brain in sepsis: involvement of theannexin1 FPR2/ALX anti-inflammatory system. FASEB 2012; 26: 1-13).

Activation of FPR2 by lipoxin A4 or its analogs and by Annexin I proteinhas been shown to result in anti-inflammatory activity by promotingactive resolution of inflammation which involves inhibition ofpolymorphonuclear neutrophils (PMNs) and eosinophils migration and alsostimulate monocyte migration enabling clearance of apoptotic cells fromthe site of inflammation in a nonphlogistic manner (Gavins FNE, Hughes EL, Buss NAPS, Holloway P M, Getting S J, Buckingham J C. Leukocyterecruitment in the brain in sepsis: involvement of the annexin1 FPR2/ALXanti-inflammatory system. FASEB 2012; 26: 1-13, Maderna P, Cotten D C,Toivonen T, Dufton N, Dalli J, Perretti M, Godson C. FPR2/ALX receptorexpression and internalization are critical for lipoxin A4 andannexin-derived peptide-stimulated phagocytosis. FASEB 2010; 24:4240-4249). In addition, FPR2 has been shown to inhibit natural killer(NK) cytotoxicity and promote activation of T cells which furthercontributes to down regulation of tissue damaging inflammatory signals.FPR2 interaction with LXA4 and Annexin has been shown to be beneficialin experimental models of dermal inflammation, angiogenesis, epithelialmigration, edema, alopecia and corneal wound healing. (Reville K, CreamJ K, Vivers S, Dransfield I, Godson C. Lipoxin A4 redistributes MyosinIIA and Cdc42 in macrophages: Implications for phagocytosis of apoptoticleukocytes. Journal of Immunology 2006; 176: 1878-1888; Serhan C.Resolution phase of inflammation: Novel endogenous anti-inflammatory andproresolving lipid mediators and pathways. Annual reviews of Immunology2007; 25: 101-137; Takano T, Fiore S, Maddox J F, Brady H R, Petasis NA, Serhan C N. Aspirin-triggered 15-epi-lipoxin A4 and LXA4 stableanalogues are potent inhibitors of acute inflammation: evidence foranti-inflammatory receptors. Journal of Experimental Medicine 1997; 185:1693-1704; Leoni G, Alam A, Neumann P A, Lambeth J D, Cheng G, McCoy J,Hilgarth R S, Kundu K, Murthy N, Kusters D, Reutelingsperger C, PerrettiM, Parkos C A, Neish A S, Nusrat A. Annexin A1, formyl peptide receptor,and NOX1 orchestrate epithelial repair. Journal of ClinicalInvestigation. 2013; 123:443-54; Leedom A, Sullivan A B, Dong B, Lau D,Gronert K. Endogenous LXA4 circuits are determinants of pathologicalangiogenesis in response to chronic injury. American Journal ofPathology 2010; 176: 74-84; Tsuruki T, Takahata K, Yoshikawa M.Mechanism of the protective effect of intraperitoneally administeredagonists for formyl peptide receptors against chemotherapy-inducedalopecia. Biosci Biotechnology Biochemistry. 2007; 71:1198-202).

Targeting FPR2 selectively would also have benefits in skin woundhealing given its potent anti-inflammatory and pro-epithelial repairrole. In addition, some skin diseases have been shown to have anabnormal expression of LL37, a pro-inflammatory cathelicidin which hasbeen shown to be a natural ligand of FPR2. In the chronic inflammatorydisease Rosacea, LL37 is highly expressed and is believed to play a keyrole in the pathogenesis (Yamasaki K, Di Nardo A, Bardan A, Murakami M,Ohtake T, Coda A, Dorschner R A, Bonnart C, Descargues P, Hovnanian A,Morhenn V B, Gallo R L. Increased serine protease activity andcathelicidin promotes skin inflammation in rosacea. Nature Medicine.2007; 13:975-80).

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to a method for treating dermalinflammation and dermal diseases by local or systemic delivery, in asubject in need of such treatment, which comprises administering apharmaceutical composition comprising a therapeutically effective amountof at least one agonist of Formyl peptide receptor 2 (FPR2).

Given the anti-inflammatory axis of LXA4-FPR2 we propose that FPR2agonists will be useful in inhibiting LL-37-mediated inflammatorydiseases such as Rosacea. Pharmaceutical utility of lipoxin A4 and itsanalogs are hampered by inherent physicochemical properties of thenatural poly-olefinic natural product. Therefore, small moleculeanti-inflammatory agonists of FPR2 would have a wide variety oftherapeutic benefit in inflammatory disorders especially in the skin.FPR2 is widely expressed in human skin and its appendages. FPR2 thusrepresents an important novel pro-resolutionary molecular target for thedevelopment of new therapeutic agents in dermatological diseases withexcessive inflammatory responses.

The invention pertains to the ability of FPR2 agonists to exhibit dermalanti-inflammatory activity with chemical stability and suitable fortopical dermal delivery. These FPR2 compounds show good potency at thereceptor and, importantly, the FPR2 compounds are topically active, andtherefore could be administered in many forms, including but not limitedto creams, lotions, gels, solutions, sprays, and foams. These compoundsmay also be administered IV, intramuscularly, intrathecally,subcutaneously, orally or intraperitoneally. These compounds will beuseful for the treatment of dermatological diseases including, but notlimited to, rosacea, rosacea fulminans, sunburn, psoriasis,menopause-associated hot flashes, flushing and redness associated withhot flashes, erythema associated with hot flashes, hot flashes resultingfrom orchiectomyatopic dermatitis, treatment of redness and itch frominsect bites, photoaging, seborrheic dermatitis, acne, allergicdermatitis, telangiectasia (dilations of previously existing small bloodvessels) of the face, angioectasias, rhinophyma (hypertrophy of the nosewith follicular dilation), acne-like skin eruptions (may ooze or crust),burning or stinging sensation, erythema of the skin, cutaneoushyperactivity with dilation of blood vessels of the skin, Lyell'ssyndrome, Stevens-Johnson syndrome, local itching and discomfortassociated with hemorrhoids, hemorrhoids, erythema multiforme minor,erythema multiforme major, erythema nodosum, eye puffiness, urticaria,pruritis, purpura, varicose veins, contact dermatitis, atopicdermatitis, nummular dermatitis, generalized exfoliative dermatitis,stasis dermatitis, lichen simplex chronicus, perioral dermatitis,pseudofolliculitis barbae, granuloma annulare, actinic keratosis, basalcell carcinoma, squamous cell carcinoma, eczema, dermal wound healing,hypertrophic scars, keloids, burns, rosacea, atopic dermatitis, acne,psoriasis, seborrheic dermatitis, actinic keratoses, basal cellcarcinoma, squamous cell carcinoma, melanoma, viral warts, photoaging,photodamage, melasma, post-inflammatory hyperpigmentation, otherdisorders of pigmentation, and alopecia (scarring and non-scarringforms). The compounds below would be expected to have therapeuticeffects in many different types of skin disease, but have beenexemplified by demonstrating accelerated wound healing activity in amouse dermal wound healing model (FIG. 1), and reduction ofLL-37-induced inflammation in mice (FIG. 2) and human keratinocytes(FIG. 2). Anti-inflammatory activity in the LL-37-induced rosacea mousemodel has been exemplified with three FPR2 agonists:{[(2S)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}aceticacid,{[(2S,3S)-2-{[(4-bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino}aceticacid,{[(2S)-2-{[(4-bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}aceticacid. Skin penetration of FPR2 agonists following topical administrationhas also been demonstrated (FIG. 3).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 FPR2 agonists show potent wound healing in a mouse model of punchdermal wound.

FIG. 2 FPR2 agonists block inflammation induced by LL-37 in mouse earsp<0.05 vs. vehicle, at all-time points.

FIG. 3. Absorption of FPR2 agonists in an in vitro human skinpenetration model.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method for treating dermatologicalinflammation and dermatological diseases in a subject in need of suchtreatment, which comprises administering a pharmaceutical compositioncomprising a therapeutically effective amount of at least one agonist ofFormyl peptide receptor 2 (FPR2).

In another aspect, the invention provides the use of at least oneagonist of FPR2 for the manufacture of a medicament for the treatment ofa dermatological inflammation disease or condition mediated by FPR2 in amammal

In another aspect, the invention provides a method for treatingdermatological inflammatory diseases, which comprises administering apharmaceutical composition comprising a therapeutically effective amountof at least one agonist of FPR2 as disclosed in U.S. patent applicationSer. No. 13/668,835, provided that the compounds have binding activityat the FPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/668,835 forthe manufacture of a medicament for the treatment of a dermatologicaldisease or condition mediated by FPR2 in a mammal, provided that thecompounds have binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/668,835 fortreating a dermatological disease or condition mediated by FPR2 in amammal, provided that the compounds have binding activity at the FPR2receptor.

The compounds disclosed in U.S. patent application Ser. No. 13/668,835are represented by Formula I:

wherein:R¹ is sec-butyl, C₆₋₁₀ aryl, —CH₂—(C₆₋₁₀)aryl, —CH₂-heterocycle, C₄₋₈cycloalkyl or C₃₋₈ cycloalkenyl or heterocycle;R² is halogen or methyl;R³ is halogen;R⁴ is H, methyl or halogen;R⁵ is OR⁶ or NH₂; andR⁶ is H or C₂₋₄ alkyl.

In another aspect, the invention provides a method for treatingdermatological inflammatory diseases, which comprises administering apharmaceutical composition, comprising a therapeutically effectiveamount of at least one agonist of FPR2 as disclosed in U.S. patentapplication Ser. No. 13/523,579, provided that the compounds havebinding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/523,579 forthe manufacture of a medicament for the treatment of a dermatologicaldisease or condition mediated by FPR2 in a mammal, provided that thecompounds have binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/523,579 fortreating a dermatological disease or condition mediated by FPR2 in amammal, provided that the compounds have binding activity at the FPR2receptor.

The compounds disclosed in U.S. patent application Ser. No. 13/523,579are represented by Formula II:

wherein:a is 1 and b is 0;a is 0 and b is 1;a is 1 and b is 1;R¹ is optionally substituted C₁₋₈ alkyl, optionally substituted C₃₋₈cycloalkyl, optionally substituted heterocycle, optionally substitutedC₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl, optionallysubstituted C₃₋₈ cycloalkenyl, —NR¹¹R¹² or —OR¹³;R² is optionally substituted C₁₋₈ alkyl or optionally substituted C₆₋₁₀aryl;R³ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁴ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁵ is halogen, —CF₃ or —S(O)_(n)R¹⁴;n is 0, 1 or 2;R⁶ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁷ is hydrogen, optionally substituted C₁₋₈ alkyl, halogen, —COOR¹⁵,—OR¹³, —NR¹¹R¹², NO₂, optionally substituted heterocycle, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl oroptionally substituted C₃₋₈ cycloalkenyl;R⁸ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R⁹ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R¹⁰ is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R^(9a) is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R^(10a) is hydrogen, optionally substituted C₁₋₈ alkyl or optionallysubstituted C₆₋₁₀ aryl;R¹¹ is hydrogen or optionally substituted C₁₋₈ alkyl;R¹² is hydrogen or optionally substituted C₁₋₈ alkyl;R¹³ is hydrogen or optionally substituted C₁₋₈ alkyl;R¹⁴ is hydrogen, CF₃ or optionally substituted C₁₋₈ alkyl; andR¹⁵ is hydrogen or optionally substituted C₁₋₈ alkyl.

In another aspect, the invention provides a method for treatingdermatological inflammatory diseases, which comprises administering apharmaceutical composition, comprising a therapeutically effectiveamount of at least one agonist of FPR2 as disclosed in U.S. patentapplication Ser. No. 13/673,800, provided that the compounds havebinding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least a compoundas disclosed in U.S. patent application Ser. No. 13/673,800 for themanufacture of a medicament for the treatment of a dermatologicaldisease or condition mediated by FPR2 in a mammal, provided that thecompounds have binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least a compoundas disclosed in U.S. patent application Ser. No. 13/673,800 for treatinga dermatological disease or condition mediated by FPR2 in a mammal,provided that the compounds have binding activity at the FPR2 receptor.

The compounds disclosed in U.S. patent application Ser. No. 13/673,800are represented by Formula III:

wherein:R¹ is halogen, hydrogen, optionally substituted C₁₋₈ alkyl, OR⁹,C(O)R¹⁰, NO₂, NR¹³R¹⁴, CN, SR¹⁵ or SO₂R¹⁶;R² is halogen, optionally substituted C₁₋₈ alkyl, CF₃, OR⁹, C(O)R¹⁰,NO₂, NR¹³R¹⁴, CN, SR¹⁵ or SO₂R¹⁶;R³ is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₃₋₈ cycloalkenyl,optionally substituted C₆₋₁₀ aryl, optionally substituted heterocycle,or together with R⁵ forms a 10- or 11-membered polycyclic ring which isoptionally substituted;R⁴ is hydrogen, optionally substituted C₁₋₈ alkyl,

optionally substituted C₃₋₈ cycloalkyl, optionally substituted C₃₋₈cycloalkenyl, optionally substituted C₆₋₁₀ aryl, optionally substitutedheterocycle, or together with R⁵ forms a spiro monocyclic or polycyclic,carbocyclic or heterocyclic, saturated or unsaturated 5 to 10 memberring which is optionally substituted;R⁵ is hydrogen, optionally substituted C₁₋₈ alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₃₋₈ cycloalkenyl,optionally substituted C₆₋₁₀ aryl, optionally substituted heterocycle,or together with R⁴ forms a spiro monocyclic or polycyclic, carbocyclicor heterocyclic, saturated or unsaturated 5 to 10 member ring which isoptionally substituted or together with R³ forms a 5 or 6 member ringwhich is optionally substituted;R⁶ is halogen, hydrogen, optionally substituted C₁₋₈ alkyl, OR⁹,C(O)R¹⁰, NO₂, NR¹³R¹⁴, CN, SR¹⁵ or SO₂R¹⁶;R⁷ is halogen, hydrogen, optionally substituted C₁₋₈ alkyl, OR⁹,C(O)R¹⁰, NO₂, NR¹³R¹⁴, CN, SR¹⁵ or SO₂R¹⁶;R⁸ is halogen, hydrogen, optionally substituted C₁₋₈ alkyl, OR⁹,C(O)R¹⁰, NO₂, NR¹³R¹⁴, CN, SR¹⁵ or SO₂R¹⁶;R⁹ is hydrogen, C(O)(C₁₋₈ alkyl) or optionally substituted C₁₋₈ alkyl;R¹⁰ is hydrogen, optionally substituted C₁₋₈ alkyl, O(C₁₋₈ alkyl),NR¹¹R¹² or OH;R¹¹ is hydrogen, optionally substituted C₆₋₁₀ aryl or optionallysubstituted C₁₋₈ alkyl;R¹² is hydrogen, optionally substituted C₆₋₁₀ aryl or optionallysubstituted C₁₋₈ alkyl;R¹³ is hydrogen, optionally substituted C₆₋₁₀ aryl or optionallysubstituted C₁₋₈ alkyl;R¹⁴ is hydrogen, optionally substituted C₆₋₁₀ aryl, optionallysubstituted C₁₋₈ alkyl, C(O)(C₁₋₈ alkyl) or SO₂(C₁₋₈ alkyl);R¹⁵ is hydrogen, optionally substituted C₁₋₈ alkyl or O(C₁₋₈ alkyl);R¹⁶ is OH, O(C₁₋₈ alkyl), (C₁₋₈ alkyl) or NR¹¹R¹²;R¹⁷ is hydrogen, optionally substituted C₆₋₁₀ aryl or optionallysubstituted C₁₋₈ alkyl;R¹⁸ is hydrogen, C(O)(C₁₋₈ alkyl), optionally substituted C₆₋₁₀ aryl, oroptionally substituted C₁₋₈ alkyl;R¹⁹ is hydrogen, C(O)(C₁₋₈ alkyl), optionally substituted C₆₋₁₀ aryl oroptionally substituted C₁₋₈ alkyl;R²⁰ is hydrogen, optionally substituted C₆₋₁₀ aryl or optionallysubstituted C₁₋₈ alkyl;R²¹ is hydrogen, optionally substituted C₆₋₁₀ aryl or optionallysubstituted C₁₋₈ alkyl;n is 1, 2, 3, 4, or 5; andm is 1, 2, 3, 4, or 5.

In another aspect, the invention provides a method for treatingdermatological inflammatory diseases, which comprises administering apharmaceutical composition comprising a therapeutically effective amountof at least one agonist of FPR2 as disclosed in U.S. patent applicationSer. No. 13/765,527, provided that the compounds have binding activityat the FPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/765,527 forthe manufacture of a medicament for the treatment of a dermatologicaldisease or condition mediated by FPR2 in a mammal, provided that thecompounds have binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/765,527 fortreating a dermatological disease or condition mediated by FPR2 in amammal, provided that the compounds have binding activity at the FPR2receptor.

The compounds disclosed in U.S. patent application Ser. No. 13/765,527are represented by Formula IV:

wherein:R¹ is hydrogen, halogen, substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted C₃₋₈ cycloalkyl, substitutedor unsubstituted C₃₋₈ cycloalkenyl, substituted or unsubstitutedheterocycle or substituted or unsubstituted C₆₋₁₀ aryl, or together withR² can form an optionally substituted cyclobutyl;R² is isopropyl or together with R³ can form a substituted orunsubstituted 3 to 6 member ring heterocycle or together with R¹ canform an optionally substituted cyclobutyl, cyclopropyl; andR³ is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₃₋₈ cycloalkyl, substituted orunsubstituted C₃₋₈ cycloalkenyl, substituted or unsubstitutedheterocycle, substituted or unsubstituted C₆₋₁₀ aryl or together with R²can form a substituted or unsubstituted 3 to 6 member ring heterocycle.

In another aspect, the invention provides a method for treatingdermatological inflammatory diseases, which comprises administering atherapeutically effective amount of a pharmaceutical composition,comprising at least one agonist of FPR2 as disclosed in U.S. patentapplication Ser. No. 13/409,228, provided that the compounds havebinding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/409,228 forthe manufacture of a medicament for the treatment of a dermatologicaldisease or condition mediated by FPR2 in a mammal, provided that thecompounds have binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/409,228 fortreating a dermatological disease or condition mediated by FPR2 in amammal, provided that the compounds have binding activity at the FPR2receptor.

wherein:

is a single bond or a double bond;

is a single bond or a double bond;R¹ is H, halogen, —S(O)R¹⁰, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²,NR¹³R¹⁴, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl or hydroxyl;R² is H, halogen, —S(O)R¹⁰, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²,NR¹³R¹⁴, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl or hydroxyl;R³ is H, halogen, —S(O)R¹⁹, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²,NR¹³R¹⁴, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, C₆₋₁₀ aryl or hydroxyl;R⁴ is H or C(O)R¹²;R⁵ is H, —OC₁₋₆ alkyl, —SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl or —C₂₋₆alkynyl;R⁶ is H, —OC₁₋₆ alkyl, —SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl or —C₂₋₆alkynyl;

Y is O or S; X is O, NR, or CH₂;

R^(a) is C₆₋₁₀ aryl,

heteroaryl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl or H;R^(b) is halogen;c is 0, 1 or 2;

R⁷ is H, halogen, —S(O)R¹⁰, —S(O)₂R¹¹, nitro, hydroxyl, cyano, —OC₁₋₆alkyl, —SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²,NR¹³R¹⁴, C₃₋₈ cycloalkenyl or C₃₋₈ cycloalkyl;R⁸ is H, halogen, —S(O)R¹⁹, —S(O)₂R¹¹, cyano, —OC₁₋₆ alkyl, —SC₁₋₆alkyl, —C₁₋₆ alkyl, C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹², NR¹³R¹⁴, C₃₋₈cycloalkenyl or C₃₋₈ cycloalkyl;R⁹ is H, —S(O)₂R¹¹, —OC₁₋₆ alkyl, —SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆alkenyl, —C₂₋₆ alkynyl, C(O)R¹², C₃₋₈ cycloalkenyl or C₃₋₈ cycloalkyl;R¹⁰ is —C₁₋₆ alkyl, C₃₋₈ cycloalkyl, or C₃₋₈ cycloalkenyl;R¹¹ is H, hydroxyl, —C₁₋₆ alkyl, C₃₋₈ cycloalkyl or C₃₋₈ cycloalkenyl;R¹² is H, hydroxyl, —C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl,NR¹³R¹⁴ or —OC₁₋₆ alkyl;R¹³ is H, —C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, SO₂R¹¹ orC(O)R¹⁵;R¹⁴ is H, —C₁₋₆ alkyl, C₃₋₈ cycloalkenyl, aryl, heterocycle or C₃₋₈cycloalkyl;R¹⁵ is H, —C₁₋₆ alkyl, C₃₋₈ cycloalkenyl or C₃₋₈ cycloalkyl; andR is H, —C₁₋₆ alkyl, C₃₋₈ cycloalkenyl or C₃₋₈ cycloalkyl;with the proviso:when “

” is a double bond then R⁵ and R⁶ are void.

In another aspect, the invention provides a method for treatingdermatological inflammatory diseases, which comprises administering apharmaceutical composition, comprising a therapeutically effectiveamount of at least one agonist of FPR2 as disclosed in U.S. patentapplication Ser. No. 13/370,472, provided that the compounds havebinding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/370,472 forthe manufacture of a medicament for the treatment of a dermatologicaldisease or condition mediated by FPR2 in a mammal, provided that thecompounds have binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/370,472 fortreating a dermatological disease or condition mediated by FPR2 in amammal, provided that the compounds have binding activity at the FPR2receptor.

The compounds as disclosed in U.S. patent application Ser. No.13/370,472 are represented by Formula VI:

wherein:A is C₆₋₁₀ aryl, heterocyle, C₃₋₈ cycloalkyl or C₃₋₈ cycloalkenyl;R¹⁷ is C₁₋₆ alkyl or

B is C₆₋₁₀ aryl, heterocyle, C₃₋₈ cycloalkyl or C₃₋₈ cycloalkenyl;R¹ is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²,NR¹³R¹⁴, C₃₋₈ cycloalkyl or hydroxyl;R² is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²,NR¹³R¹⁴, C₃₋₈ cycloalkyl or hydroxyl;R³ is H, C₁₋₆ alkyl or C₃₋₈ cycloalkyl;R⁴ is H, C₁₋₆ alkyl or C₃₋₈ cycloalkyl;R^(5a) is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆alkyl, —C₁₋₆alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹², NR¹³R¹⁴,C₃₋₈ cycloalkyl or hydroxyl;R^(5b) is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²,NR¹³R¹⁴, C₃₋₈ cycloalkyl or hydroxyl;R^(5c) is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆alkyl, —C₁₋₆alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹², NR¹³R¹⁴,C₃₋₈ cycloalkyl or hydroxyl;R^(5d) is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆ alkyl, —C₁₋₆alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²,NR¹³R¹⁴, C₃₋₈ cycloalkyl or hydroxyl;R⁶ is H, —S(O)₂R¹¹, —C₁₋₆ alkyl, —(CH₂)_(n)NR¹³R¹⁴, —(CH₂)_(m)heterocycle, C(O)R¹², NR¹³R¹⁴, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl, orheterocycle;R⁷ is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²,NR¹³R¹⁴, C₃₋₈ cycloalkyl or hydroxyl;R⁸ is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²,NR¹³R¹⁴, C₃₋₈ cycloalkyl or hydroxyl;R⁹ is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²,NR¹³R¹⁴, C₃₋₈ cycloalkyl or hydroxyl;R¹⁰ is H, halogen, —S(O)R¹⁵, —S(O)₂R¹¹, nitro, cyano, —OC₁₋₆ alkyl,—SC₁₋₆ alkyl, —C₁₋₆ alkyl, —C₂₋₆ alkenyl, —C₂₋₆ alkynyl, C(O)R¹²,NR¹³R¹⁴, C₃₋₈ cycloalkyl or hydroxyl;

X is O or S; Y is O or S;

R¹¹ is H, hydroxyl, —C₁₋₆ alkyl, C₃₋₈ cycloalkyl or NR¹³R¹⁴;R¹² is H, hydroxyl, —C₁₋₆ alkyl, hydroxyl, C₃₋₈ cycloalkyl, NR¹³R¹⁴ or—OC₁₋₆ alkyl;R¹³ is H, C₃₋₈ cycloalkyl, SO₂R¹¹ or C(O)R¹⁶;R¹⁴ is H, —C₁₋₆ alkyl or C₃₋₈ cycloalkyl;R¹⁵ is —C₁₋₆ alkyl, or C₃₋₈ cycloalkyl;R¹⁶ is H, —C₁₋₆ alkyl or C₃₋₈ cycloalkyl;n is 1-4; andm is 1-4.

In another aspect, the invention provides a method for treatingdermatological inflammatory diseases, which comprises administering apharmaceutical composition, comprising a therapeutically effectiveamount of at least one agonist of FPR2 as disclosed in U.S. patentapplication Ser. No. 13/863,934, provided that the compounds havebinding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/863,934 forthe manufacture of a medicament for the treatment of a dermatologicaldisease or condition mediated by FPR2 in a mammal, provided that thecompounds have binding activity at the FPR2 receptor.

In another aspect, the invention provides the use of at least onecompound as disclosed in U.S. patent application Ser. No. 13/863,934 fortreating a dermatological disease or condition mediated by FPR2 in amammal, provided that the compounds have binding activity at the FPR2receptor.

The compounds as disclosed in U.S. patent application Ser. No.13/863,934 are represented by Formula VII:

wherein:n is 0 or 1;R¹ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, halogen,—NR⁸R⁹, —NC(O)R²⁰, —OR¹⁰, —OC(O)R²¹, —SR¹¹, —C(O)R¹², CN or NO₂;R² is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, halogen,—NR⁸R⁹, —NC(O)R²⁰, —OR¹⁰, —OC(O)R²¹, —SR¹¹, —C(O)R¹², CN or NO₂;R³ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, halogen,—NR⁸R⁹, —NC(O)R²⁰, —OR¹⁰, —OC(O)R²¹, —SR¹¹, —C(O)R¹², CN, NO₂, CF₃,S(O)R¹⁵ or S(O)₂R¹⁶;R⁴ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, halogen,—NR⁸R⁹, —NC(O)R²⁰, —OR¹⁰, —OC(O)R²¹, —SR¹¹, —C(O)R¹², CN or NO₂;R⁵ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, halogen,—NR⁸R⁹, —NC(O)R²⁰, —OR¹⁰, —OC(O)R²¹, SR¹¹, —C(O)R¹², CN or NO₂;R⁶ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted heterocycle, substituted or unsubstituted C₃₋₈ cycloalkyl,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstitutedC₃₋₈ cycloalkenyl or —CH₂R¹⁹;R⁷ is substituted or unsubstituted heterocycle, —SR¹¹, —NR⁸R⁹,—N(H)C(O)N(H)S(O)₂R¹⁹, —BR¹³R¹⁴, —S(O)R¹⁵, —C(O)N(H)(CN),—C(O)N(H)S(O)₂R¹⁹, —S(O)(N)(PO₃H₂), —S(O)₂R¹⁶ or —P(O)R¹⁷R¹⁸;R⁸ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted heterocycle,or substituted or unsubstituted C₆₋₁₀ aryl;R⁹ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted heterocycle,or substituted or unsubstituted C₆₋₁₀ aryl;R¹⁰ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;R¹¹ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl or —CF₃;R¹² is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, hydroxyl,—OR²⁴ or —NR⁸R⁹;R¹³ is —OR²²;R¹⁴ is —OR²³;R¹⁵ is substituted or unsubstituted C₁₋₈ alkyl;R¹⁶ is substituted or unsubstituted C₁₋₈ alkyl, —NR⁸R⁹, —NHS(O)₂R¹⁹ orhydroxyl;R¹⁷ is OR¹⁰ or NR⁸R⁹;R¹⁸ is OR¹⁰ or NR⁸R⁹;R¹⁹ is substituted or unsubstituted heterocycle, substituted orunsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted C₆₋₁₀ arylor substituted or unsubstituted C₃₋₈ cycloalkenyl;R²⁰ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted heterocycle,or substituted or unsubstituted C₆₋₁₀ aryl;R²¹ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl substituted orunsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted heterocycle,or substituted or unsubstituted C₆₋₁₀ aryl;R²² is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, or togetherwith R²³ can form a cycle;R²³ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, or togetherwith R²² can form a cycle; andR²⁴ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted heterocycle,or substituted or unsubstituted C₆₋₁₀ aryl.

The term “alkyl”, as used herein, refers to saturated, monovalent ordivalent hydrocarbon moieties having linear or branched moieties orcombinations thereof and containing 1 to 8 carbon atoms. One methylene(—CH₂—) group, of the alkyl group can be replaced by oxygen, sulfur,sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate,amide, sulfonamide, by a divalent C₃₋₈ cycloalkyl, by a divalentheterocycle, or by a divalent aryl group. Alkyl groups can have one ormore chiral centers. Alkyl groups can be independently substituted byhalogen atoms, hydroxyl groups, cycloalkyl groups, amino groups,heterocyclic groups, aryl groups, carboxylic acid groups, phosphonicacid groups, sulphonic acid groups, phosphoric acid groups, nitrogroups, amide groups, sulfonamide groups.

The term “cycloalkyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms derived from a saturated cyclichydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic.Cycloalkyl can be independently substituted by halogen atoms, sulfonylC₁₋₈ alkyl groups, sulfoxide C₁₋₈ alkyl groups, sulfonamide groups,nitro groups, cyano groups, —OC₁₋₈ alkyl groups, —SC₁₋₈ alkyl groups,—C₁₋₈ alkyl groups, —C₂₋₆ alkenyl groups, —C₂₋₆ alkynyl groups, ketonegroups, alkylamino groups, amino groups, aryl groups, C₃₋₈ cycloalkylgroups or hydroxyl groups.

The term “cycloalkenyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms derived from a saturatedcycloalkyl having at least one double bond. Cycloalkenyl groups can bemonocyclic or polycyclic. Cycloalkenyl groups can be independentlysubstituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitrogroups, cyano groups, —OC₁₋₆ alkyl groups, —SC₁₋₆ alkyl groups, —C₁₋₆alkyl groups, —C₂₋₆ alkenyl groups, —C₂₋₆ alkynyl groups, ketone groups,alkylamino groups, amino groups, aryl groups, C₃₋₈ cycloalkyl groups orhydroxyl groups.

The term “halogen”, as used herein, refers to an atom of chlorine,bromine, fluorine, iodine.

The term “alkenyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one double bond. One methylene (—CH₂—) group, ofthe alkenyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen,carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, bya divalent C₃₋₈ cycloalkyl, by a divalent heterocycle, or by a divalentaryl group. C₂₋₆ alkenyl can be in the E or Z configuration. Alkenylgroups can be substituted by alkyl groups, as defined above or byhalogen atoms.

The term “alkynyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one triple bond. One methylene (—CH₂—) group, ofthe alkynyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen,carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, bya divalent C₃₋₈ cycloalkyl, by a divalent heterocycle, or by a divalentaryl group. Alkynyl groups can be substituted by alkyl groups, asdefined above, or by halogen atoms.

The term “heterocycle” as used herein, refers to a 3 to 10 memberedring, which can be aromatic or non-aromatic, saturated or unsaturated,containing at least one heteroatom selected form oxygen, nitrogen,sulfur, or combinations of at least two thereof, interrupting thecarbocyclic ring structure. The heterocyclic ring can be interrupted bya C═O; the S and N heteroatoms can be oxidized. Heterocycles can bemonocyclic or polycyclic. Heterocyclic ring moieties can be substitutedby halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyanogroups, —OC₁₋₆ alkyl groups, —SC₁₋₆ alkyl groups, —C₁₋₈ alkyl groups,—C₂₋₆ alkenyl groups, —C₂₋₆ alkynyl groups, ketone groups, alkylaminogroups, amino groups, aryl groups, C₃₋₈ cycloalkyl groups or hydroxylgroups.

The term “aryl” as used herein, refers to an organic moiety derived froman aromatic hydrocarbon consisting of a ring containing 6 to 10 carbonatoms, by removal of one hydrogen atom. Aryl can be substituted byhalogen atoms, sulfonyl C₁₋₆ alkyl groups, sulfoxide C₁₋₆ alkyl groups,sulfonamide groups, carboxylic acid groups, C₁₋₆ alkyl carboxylates(ester) groups, amide groups, nitro groups, cyano groups, —OC₁₋₆ alkylgroups, —SC₁₋₆ alkyl groups, —C₁₋₆ alkyl groups, —C₂₋₆ alkenyl groups,—C₂₋₆ alkynyl groups, ketone groups, aldehydes, alkylamino groups, aminogroups, aryl groups, C₃₋₈ cycloalkyl groups or hydroxyl groups. Arylscan be monocyclic or polycyclic.

The term “hydroxyl” as used herein, represents a group of formula “—OH”.

The term “carbonyl” as used herein, represents a group of formula“—C(O)—”.

The term “ketone” as used herein, represents an organic compound havinga carbonyl group linked to a carbon atom such as —(CO)R^(x), whereinR^(x) can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle asdefined above.

The term “amine” as used herein, represents a group of formula“—NR^(x)R^(y)”, wherein R^(x) and R^(y) can be the same or independentlyH, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

The term “carboxyl” as used herein, represents a group of formula“—C(O)O—”.

The term “sulfonyl” as used herein, represents a group of formula “—SO₂⁻”.

The term “sulfate” as used herein, represents a group of formula“—O—S(O)₂—O—”.

The term “sulfonate” as used herein, represents a group of the formula“—S(O)₂—O—”.

The term “carboxylic acid” as used herein, represents a group of formula“—C(O)OH”.

The term “nitro” as used herein, represents a group of formula “—NO₂”.

The term “cyano” as used herein, represents a group of formula “—CN”.

The term “amide” as used herein, represents a group of formula“—C(O)NR^(x)R^(y)” wherein R^(x) and R^(y) can be the same orindependently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle asdefined above.

The term “sulfonamide” as used herein, represents a group of formula“—S(O)₂NR^(x)R^(y)” wherein R^(x) and R^(y) can be the same orindependently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle asdefined above.

The term “sulfoxide” as used herein, represents a group of formula“—S(O)—”.

The term “phosphonic acid” as used herein, represents a group of formula“—P(O)(OH)₂”.

The term “phosphoric acid” as used herein, represents a group of formula“—OP(O)(OH)₂”.

The term “sulphonic acid” as used herein, represents a group of formula“—S(O)₂OH”.

The formula “H”, as used herein, represents a hydrogen atom.

The formula “O”, as used herein, represents an oxygen atom.

The formula “N”, as used herein, represents a nitrogen atom.

The formula “S”, as used herein, represents a sulfur atom.

In another aspect, agonists of FPR2 are compounds selected from Table 1:

TABLE 1 FPRL-1 Ga16-CHO EC₅₀ Structure IUPAC name (efficacy)

2-({[(4- chlorophenyl)amino]carbonyl}amino)-3- phenylpropanoic acid 110nM (1.0)

(2S)-2-({[(4- methoxyphenyl)amino]carbonyl}amino)-3- phenylpropanoicacid 1754 nM (0.90)

(2S)-3-phenyl-2-[({[4- (trifluoromethyl)phenyl]amino}carbonyl)amino]propanoic acid 120 nM (0.97)

(2S)-2-({[(3,4- dichlorophenyl)amino]carbonyl}amino)-3- phenylpropanoicacid 10 □M (0.57)

(2S)-2-({[(4- nitrophenyl)amino]carbonyl}amino)-3- phenylpropanoic acid574 nM (0.82)

3-phenyl-2-[({[4- (tririuoromethoxy)phenyl]amino}carbonyl)amino]propanoic acid 1572 nM (0.79)

2-({[(3,4- dimethoxyphenyl)amino]carbonyl}amino)- 3-phenylpropanoic acid2793 nM (0.72)

methyl 2-({[(4- iodophenyl)amino]carbonyl}amino)-3- phenylpropanoate14.3 nM (1.0)

(2S)-2-({[(4- bromophenyl)amino]carbonyl}amino)-3- phenylpropanoic acid31 nM (1.0)

(2R)-2-({[(4- bromophenyl)amino]carbonyl}amino)-3- phenylpropanoic acid1819 nM (0.99)

3-phenyl-2-{[(pyridin-3- ylamino)carbonyl]amino}propanoic acid

(2S,3S)-2-({[(4- bromophenyl)amino]carbonyl}amino)-3- methylpentanoicacid 4.1 nM (0.89)

(2S)-({[(4- bromophenyl)amino]carbonyl}amino) (phenyl)acetic acid 25.8nM (0.94)

2-({[(4- bromophenyl)amino]carbonyl}amino)-3- (lH-indol-3-yl)propanoicacid 67.0 nM (0.89)

(2S)-2-({[(4- bromophenyl)amino]carbonyl}amino)-3- methylbutanoic acid72 nM (0.91)

(2S)-2-({[(4-bromo-2- fluorophenyl)amino]carbonyl}amino)-3-methylbutanoic acid 152 nM (0.91)

US 2005/0137230 A1 and U.S. Pat. No. 7,820,673 disclose inhibitors ofcoagulation Factor Xa and can be employed for the prophylaxis and/ortherapy of thromboembolic diseases and/or the treatment of tumors.2-({[(4-chlorophenyl)amino]carbonyl}amino)-3-phenylpropanoic acid,(2S)-2-({[(4-methoxyphenyl)amino]carbonyl}amino)-3-phenylpropanoic acid,(2S)-3-phenyl-2-[({[4-(trifluoromethyl)phenyl]amino}carbonyl)amino]propanoicacid, methyl2-({[(4-iodophenyl)amino]carbonyl}amino)-3-phenylpropanoate,(2S)-2-({[(4-bromophenyl) amino]carbonyl}amino)-3-phenylpropanoic acid,(2R)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-phenylpropanoic acid,are intermediates in the synthesis of urea derivatives as activatedblood coagulation factor X (FXa) inhibitors.

JP 63232846 discloses the resolution of N-(p-bromophenylcarbamyl)derivatives((2S)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-phenylpropanoic acid,(2S,3S)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-methylpentanoicacid,2-({[(4-bromophenyl)amino]carbonyl}amino)-3-(1H-indol-3-yl)propanoicacid, (2S)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-methylbutanoicacid) on HPLC column with novel chromatographic chiral stationaryphases.

Journal of Chromatography (1987), 404(1), 117-22 and Chromatographia(1987), 23(10), 727-30 describe the resolution of p-Bromophenylcarbamylderivatives of enantiomeric protein amino acids((2R)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-phenylpropanoic acid,(2S)-2-({[(4-bromophenyl)amino]carbonyl}amino)-3-phenylpropanoic acid),on novel chiral stationary phase by elution with an aqueous mobilephase.

Biochimica et Biophysica Acta, Nucleic Acids and Protein Synthesis(1972), 272(4), 667-71 describes compound(2S)-2-({[(4-nitrophenyl)amino]carbonyl}amino)-3-phenylpropanoic acid)in poly(uridylic acid)-dependent binding of paranitrophenyl-carbamyl-phenylalanyl tRNA.

In another aspect, agonists of FPR2 are compounds selected from Table 2:

TABLE 2 FPRL-1 Ga16-CHO EC50 Structure IUPAC name (efficacy)

1-(4-chlorophenyl)-3-(2,4-dioxo-1,3- diazaspiro[4,5]decan-3-yl)urea 49nM (0.98)

1-(4-chlorophenyl)-3-(4-ethyl-4- methyl-2,5-dioxoimidazolidin-1- yl)urea157 nM (0.96)

1-[4-methyl-2,5-dioxo-4-(2- phenylethyl)imidazolidin-1-yl]-3- phenylurea223 nM (1.0)

1-(8-methyl-2,4-dioxo-1,3- diazaspiro[4,5]decan-3-yl)-3-(p- tolyl)urea363 nM (0.91)

1-(2-fluorophenyl)-3-[4-methyl-2,5- dioxo-4-(2-phenylethyl)imidazolidin-1-yl]urea 258 nM (0.94)

Compounds of Table 2 are available from Chemical Libraries such asAurora Fine Chemicals.

In another aspect, agonists of FPR2 are compounds selected from Table 3:

TABLE 3 FPRL-1 Ga16-CHO EC₅₀ Structure IUPAC name (efficacy)

N-(4-bromophenyl)-2-(4,4-dimethyl- 2,5-dioxoimidazolidin-1-yl)acetamide719 nM (0.94)

N-(4-bromophenyl)-2-(4,4-diethyl-2,5- dioxoimidazolidin-1-yl)acetamide96 nM (0.98)

N-(4-bromophenyl)-2-(2,4-dioxo-1,3- diazaspiro[4.5]dec-3-yl)acetamide738 nM (0.89)

N-(4-bromophenyl)-2-(2,4-dioxo-1,3- diazaspiro[4.4]non-3-yl)acetamide322 nM (0.96)

N-(4-bromophenyl)-2-(2,5-dioxo-4,4- dipropylimidazolidin-1-yl)acetamide645 nM (0.98)

N-(4-bromophenyl)-2-(4-ethyl-2,5- dioxo-4-phenylimidazolidin-1-yl)acetamide 523 nM (0.83)

N-(4-bromophenyl)-2-(4-cyclopropyl-4- methyl-2,5-dioxoimidazolidin-1-yl)acetamide 166 nM (0.84)

N-(4-bromophenyl)-2-(2,4-dioxo-1,3- diazaspiro[4.6]undec-3-yl)acetamide679 nM (0.96)

N-(4-bromophenyl)-2-(4-ethyl-4- methyl-2,5-dioxoimidazolidin-1-yl)acetamide 485 nM (1.0)

N-(4-chlorophenyl)-2-(4,4-diethyl-2,5- dioxoimidazolidin-1-yl)acetamide314 nM (0.79)

2-(4,4-diethyl-2,5-dioxoimidazolidin-1- yl)-N-(4-fluorophenyl)acetamide2771 nM (0.67)

N-(4-bromophenyl)-2-[4-methyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1- yl]acetamide 860 nM (0.88)

N-(4-bromophenyl)-1,3,3a,4,7,7a- hexahydro-1,3-dioxo-4,7-methano-2H-isoindole-2-acetamide 575 (0.90)

N-(4-bromophenyl)-1,3,3a,4,7,7a- hexahydro-1,3-dioxo-2H-isoindole-2-acetamide 395 (0.98)

The compounds of Table 3 are available from Chemical Libraries such asChemical Block Ltd.

In a further embodiment of the invention, there are provided methods fortreating disorders associated with modulation of the N-formyl peptidereceptor like-1 receptor.

Such methods can be performed, for example, by administering to asubject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one compound of theinvention.

Therapeutic utilities of the N-formyl peptide receptor like-1 receptormodulators are dermatological inflammation and diseases including, butnot limited to, dermal wound healing, hypertrophic scars, keloids,burns, rosacea, atopic dermatitis, acne, psoriasis, seborrheicdermatitis, actinic keratoses, basal cell carcinoma, squamous cellcarcinoma, melanoma, viral warts, photoaging, photodamage, melasma,post-inflammatory hyperpigmentation, other disorders of pigmentation,and alopecia (scarring and non-scarring forms).

These compounds are useful for the treatment of mammals, includinghumans, with a range of conditions and diseases that are alleviated bythe N-formyl peptide receptor like-1 receptor modulation: dermatologicalinflammation and diseases including, but not limited to, dermal woundhealing, hypertrophic scars, keloids, burns, rosacea, atopic dermatitis,acne, psoriasis, seborrheic dermatitis, actinic keratoses, basal cellcarcinoma, squamous cell carcinoma, melanoma, viral warts, photoaging,photodamage, melasma, post-inflammatory hyperpigmentation, otherdisorders of pigmentation, and alopecia (scarring and non-scarringforms).

In still another embodiment of the invention, there are provided methodsfor treating disorders associated with modulation of the FPRL-1receptor. Such methods can be performed, for example, by administeringto a subject in need thereof a therapeutically effective amount of atleast one compound of the invention, or any combination thereof, orpharmaceutically acceptable salts, hydrates, solvates, crystal forms andindividual isomers, enantiomers, and diastereomers thereof.

The actual amount of the compound to be administered in any given casewill be determined by a physician taking into account the relevantcircumstances, such as the severity of the condition, the age and weightof the patient, the patient's general physical condition, the cause ofthe condition, and the route of administration.

The patient will be administered the compound orally in any acceptableform, such as a tablet, liquid, capsule, powder and the like, or otherroutes may be desirable or necessary, particularly if the patientsuffers from nausea. Such other routes may include, without exception,transdermal, parenteral, subcutaneous, intranasal, via an implant stent,intrathecal, intravitreal, topical to the eye, back to the eye,intramuscular, intravenous, and intrarectal modes of delivery.Additionally, the formulations may be designed to delay release of theactive compound over a given period of time, or to carefully control theamount of drug released at a given time during the course of therapy.

In another embodiment of the invention, there are providedpharmaceutical compositions including at least one compound of theinvention in a pharmaceutically acceptable carrier thereof. The phrase“pharmaceutically acceptable” means the carrier, diluent or excipientmust be compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a patch, amicelle, a liposome, and the like, wherein the resulting compositioncontains one or more compounds of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. Inventioncompounds may be combined, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, and any other formsuitable for use. The carriers which can be used include glucose,lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Inventioncompounds are included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or diseasecondition.

Pharmaceutical compositions containing invention compounds may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known in the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting of asweetening agent such as sucrose, lactose, or saccharin, flavoringagents such as peppermint, oil of wintergreen or cherry, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets containing invention compounds inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be, forexample, (1) inert diluents such as calcium carbonate, lactose, calciumphosphate or sodium phosphate; (2) granulating and disintegrating agentssuch as corn starch, potato starch or alginic acid; (3) binding agentssuch as gum tragacanth, corn starch, gelatin or acacia, and (4)lubricating agents such as magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the invention compounds are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They may also be in the form of soft gelatin capsules whereinthe invention compounds are mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Pharmaceutical compositions containing invention compounds may be in aform suitable for topical use, for example, as oily suspensions, assolutions or suspensions in aqueous liquids or nonaqueous liquids, or asoil-in-water or water-in-oil liquid emulsions.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

The compounds of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention compounds with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner.

The compounds and pharmaceutical compositions described herein areuseful as medicaments in mammals, including humans, for treatment ofdiseases and/or alleviations of conditions which are responsive totreatment by agonists or functional antagonists of the N-formyl peptidereceptor like-1 (FPRL-1) receptor. Thus, in further embodiments of theinvention, there are provided methods for treating a disorder associatedwith modulation of the N-formyl peptide receptor like-1 (FPRL-1)receptor. Such methods can be performed, for example, by administeringto a subject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one invention compound. Asused herein, the term “therapeutically effective amount” means theamount of the pharmaceutical composition that will elicit the biologicalor medical response of a subject in need thereof that is being sought bythe researcher, veterinarian, medical doctor or other clinician. In someembodiments, the subject in need thereof is a mammal. In someembodiments, the mammal is human.

Materials and Methods

FPR2 agonists would be expected to have significant effects in manydifferent types of dermatological inflammation, but have beenexemplified by demonstrating wound healing in a mouse model of punchdermal wound (FIG. 2). Anti-inflammatory activity in this model has beenexemplified with the FPR2 agonists described in Table 4.

FLIPR: HEK-Gα16 cells stably expressing the human FPR2 receptor wasutilized. Cells were plated into 384-well poly-D-lysine coated plates ata density of 18,000 cells per well one day prior to use. The growthmedia was DMEM medium supplemented with 10% fetal bovine serum (FBS), 1%antibiotic-antimycotic, 50 μg/ml hygromycin, and 400 μg/ml geneticin. Onthe day of the experiment, the cells were washed twice with Hank'sBalanced Salt Solution supplemented with 20 mM HEPES (HBSS/hepesbuffer). The cells were then dye loaded with 2 μM Fluo-4 diluted in theHBSS/Hepes buffer and incubated at 37° C. for 40 minutes. Extracellulardye was removed by washing the cell plates four times prior to placingthe plates in the FLIPR (Fluorometric Imaging Plate Reader, MolecularDevices). Ligands were diluted in HBSS/Hepes buffer and prepared in384-well microplates. Data for Ca⁺² responses were obtained in relativefluorescence units.

TABLE 4 Com- FPR2 pound EC50 number Structure IUPAC name (% eff)  1

1-(4-bromophenyl)-3-[4-ethyl- 2,5-dioxo-4-(2-phenylethyl)imidazolidin-1- yl]urea 3.0 (0.96)  2

{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino} pentanoyl]amino}acetic acid2 (0.91)  3

{[(2S,3S)-2-{[(4- bromophenyl)carbamoyl]amino}- 3-methylpentanoyl]amino}acetic acid 1.98 (1.0)  4

1-(4-bromophenyl)-3-[4-ethyl- 2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea 6.7 (0.90)  5

(2S,3S)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}- 3-methylpentanoicacid 31 (0.96)  6

2-{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-2- methylpropanoic acid 1.66 (0.91)  7

{[(2S)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}-4-methylpentanoyl]amino} acetic acid 3.57 (1.0)  8

{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- 4-methylpentanoyl]amino}acetic acid 0.78 (0.78)  9

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- 4-methylpentanoic acid 5.95(0.77)  10

2-{[(4- bromophenyl)carbamoyl]amino}- N-(2-oxoazepan-3-yl)-3-phenylpropanamide 11 nM (0.89)  11

3-[(4- iodophenyl)carbamoyl]spiro [bicyclo[2.2.1]heptane-7,1′-cyclopropane]-5-ene-2- carboxylic acid 1.6 nM (1.00)  12

3-[(4- bromophenyl)carbamoyl]spiro [bicyclo[2.2.1]heptane-7,1′-cyclopropane]-5-ene-2- carboxylic acid 4 nM (0.97)  13

1-(4-acetylphenyl)-3-{3-(4- cyanophenyl)-2-[2-(1H-imidazol-4-yl)ethyl]-1-oxo- 1,2,3,4-tetrahydroisoquinolin-7- yl}urea 11nM (0.80)  14

rel-(2R,3S)-3-[(4- bromophenyl)carbamoyl]spiro[bicyclo[2.2.1]heptane-7,1′- cyclopropane]-2-carboxylic acid 4 nM (0.90) 15

3-[(4- iodophenyl)carbamoyl]spiro [bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2-carboxylic acid 0.60 nM (0.87)  16

1-[2-(3-aminopropyl)-3-(4- cyanophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl]-3- [4-(methylsulfanyl)phenyl]urea 2.5 nM(0.70)  17

1-{3-(4-cyanophenyl)-2-[2-(1H- imidazol-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl}-3-[4- (methylsulfanyl)phenyl]urea5.5 nM (0.92)  18

1-[2-(3-aminopropyl)-3-(4- cyanophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl]-3- [4-(methylsulfonyl)phenyl]urea 10 nM(0.86)  19

1-{3-(4-cyanophenyl)-2-[2-(1H- imidazol-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl}-3-[4- (methylsulfonyl)phenyl]urea20 nM (1.00)  20

3-[(4-iodophenyl)carbamoyl]-7- (propan-2- ylidene)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid 11 nM (0.94)  21

3-[(4-bromophenyl)carbamoyl]- 7,7- dimethylbicyclo[2.2.1]heptane-2-carboxylic acid 10 nM (0.85)  22

3-[(4-iodophenyl)carbamoyl]- 7,7- dimethylbicyclo[2.2.1]heptane-2-carboxylic acid 1.7 nM (0.97)  23

1-{3-(furan-2-yl)-2-[2-(1H- imidazol-4-yl)ethyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl}-3-[4- (methylsulfanyl)phenyl]urea19 nM (0.83)  24

1-{3-(5-fluoropyridin-2-yl)-2- [2-(1H-imidazol-4-yl)ethyl]-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl}-3-[4-(methylsulfinyl)phenyl]urea 11.8 nM (0.93)  25

1-{3-(5-fluoropyridin-2-yl)-2- [2-(1H-imidazol-4-yl)ethyl]-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl}-3-[4-(methylsulfonyl)phenyl]urea 10.5 nM (1.0)  26

N-(4- bromophenyl)spiro[bicyclo [2.2.1]heptane-7,1′- cyclopropane]-5-ene-2,3-dicarboxamide 4.8 nM (0.91)  27

1-{3-(5-chlorofuran-2-yl)-2-[2- (1H-imidazol-4-yl)ethyl]-1-oxo-l,2,3,4-tetrahydroisoquinolin-7- yl}-3-[4- (methylsulfanyl)phenyl]urea17 nM (0.81)  28

1-{3-(6-chloropyridin-3-yl)-2- [2-(1H-imidazol-4-yl)ethyl]-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl}-3-[4-(methylsulfanyl)phenyl]urea 6.3 nM (0.89)  29

3-{[4- (methylsulfanyl)phenyl] carbamoyl}spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]- 2-carboxylic acid 7 nM (0.96)  30

N-(4- bromophenyl)spiro[bicyclo [2.2.1]heptane-7,1′-cyclopropane]-2,3-dicarboxamide 2.5 nM (0.96)  31

3-{[4- (methylsulfanyl)phenyl]carbamoyl} spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-5-ene-2- carboxylic acid 14 nM (0.85)  32

1-{3-(5-chloropyridin-2-yl)-2- [2-(1H-imidazol-4-yl)ethyl]-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl}-3-[4-(methylsulfanyl)phenyl]urea 13.5 nM (0.91)  33

1-{3-(5-chloropyridin-2-yl)-2- [2-(1H-imidazol-4-yl)ethyl]-1-oxo-1,2,3,4- tetrahydroisoquinolin-7-yl}-3-[4-(methylsulfonyl)phenyl]urea 9.5 nM (0.99)  34

N-(4-bromophenyl)-7,7- dimethylbicyclo[2.2.1]heptane- 2,3-dicarboxamide15 nM (0.83)  35

N-(4-iodophenyl)-7,7- dimethylbicyclo[2.2.1]heptane- 2,3-dicarboxamide2.6 nM (0.81)  36

(+)1-[(3R)-2-(3-aminopropyl)- 3-(4-cyanophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl]-3-[4- (methylsulfanyl)phenyl]urea3.3 nM (0.97)  37

7,7-dimethyl-N-[4- (methylsulfanyl)phenyl]bicyclo [2.2.1]heptane-2,3-dicarboxamide 17 nM (0.85)  38

N-(4- iodophenyl)spiro[bicyclo[2.2.1] heptane-7,1′-cyclopropane]-2,3-dicarboxamide 1.9 nM (0.95)  39

N-(4- iodophenyl)spiro[bicyclo[2.2.1] heptane-7,1′-cyclopropane]-5-ene-2,3-dicarboxamide 1.6 nM (0.90)  40

(+) tert-butyl {3-[(3R)-3-(4- cyanophenyl)-7-({[4-(methylsulfinyl)phenyl] carbamoyl}amino)-1-oxo-3,4-dihydroisoquinolin-2(1H)- yl]propyl}carbamate 103 nM (0.91)  41

(+) 1-[(3R)-2-(3-aminopropyl)- 3-(4-cyanophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7- yl]-3-[4- (methylsulfinyl)phenyl]urea10.6 nM (0.94)  42

1-[2-(3-aminopropyl)-3-methyl- 1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl]-3- [4-(methylsulfanyl)phenyl]urea 15 nM(1.00)  43

1-[2-(3-aminopropyl)-3-(4- cyanophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl]-3- (4-iodophenyl)urea 13.7 nM (0.94)  44

(+) (2S,3R)-3-[(4- bromophenyl)carbamoyl]spiro[bicyclo[2.2.1]heptane-7,1′- cyclopropane]-2-carboxylic acid <1 nM(0.98)  45

(−) N-(4- bromophenyl)spiro[bicyclo[2.2.1] heptane-7,1′-cyclopropane]-2,3-dicarboxamide <1 nM (0.91)  46

N-(4-bromophenyl)-N′- methylspiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2,3- dicarboxamide 8.5 nM (1.0)  47

N-(4-bromophenyl)-N′- ethylspiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2,3- dicarboxamide 9.3 nM (1.0)  48

N-(4-bromophenyl)-N′-(propan- 2- yl)spiro[bicyclo[2.2.1]heptane-7,1′-cyclopropane]-2,3- dicarboxamide 6.7 nM (1.0)  49

1-(4-bromophenyl)-3-(4,4- diethyl-2,5-dioxoimidazolidin- 1-yl)urea 11.5nM (0.98)  50

1-(4-bromo-2-fluorophenyl)-3- (4,4-diethyl-2,5-dioxoimidazolidin-1-yl)urea 15.7 nM (1.0)  51

(2S)-2-{[(4- iodophenyl)carbamoyl]amino}- 3-phenylpropanoic acid 14.5 nM(1.0)  52

1-(4-bromophenyl)-3-(2,4- dioxo-1,3-diazaspiro[4.5]dec-3- yl)urea 15.1nM (1.0)  53

(2S,3S)-2-{[(4- bromophenyl)carbamoyl]amino}- 3-methylpentanoic acid12.9 nM (0.9)  54

1-(4-bromophenyl)-3-[4-methyl- 2,5-dioxo-4-(2-phenylethyl)imidazolidin-1- yl]urea 5.1 nM (0.87)  55

{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- 3-phenylpropanoyl]amino}acetic acid 7.7 nM (0.99)  56

3-{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- 3-phenylpropanoyl]amino}propanoic acid 18 nM (0.98)  57

(+) 1-(4-bromophenyl)-3-[4- methyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1- yl]urea 3.2 nM (0.93)  58

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- N-(2-hydroxyethyl)-3-phenylpropanamide 7.0 nM (0.86)  59

{[(2S,3S)-2-{[(4-bromo-2- fluorophenylcarbamoyl]amino}-3-methylpentanoyl]amino} acetic acid 5.5 nM (0.95)  60

(2S,3S)-N-(2-amino-2- oxoethyl)-2-{[(4- bromophenyl)carbamoyl]amino}-3-methylpentanamide 4.6 nM (0.91)  61

1-(4-bromo-2-fluorophenyl)-3- [4-ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea 9.2 nM (0.97)  62

(2S,3S)-N-(2-amino-2- oxoethyl)-2-{[(4-bromo-2-fluorophenyl)carbamoyl]amino}- 3-methylpentanamide 10.3 nM (1.0)  63

(2S,3S)-2-{[(4- bromophenyl)carbamoyl] amino}-3-methyl-N-(2-oxopropyl)pentanamide 10.5 nM (0.97)  64

1-(4-bromophenyl)-3-[2,5- dioxo-4,4-di(propan-2-yl)imidazolidin-1-yl]urea 3.8 nM (1.0)  65

1-(4-bromophenyl)-3-(4,4- dicyclopropyl-2,5- dioxoimidazolidin-1-yl)urea14.3 nM (1.0)  66

(+)1-(4-bromophenyl)-3-[4- ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea 4.3 nM (0.96)  67

(−)1-(4-bromophenyl)-3-[4- ethyl-2,5-dioxo-4-(propan-2-yl)imidazolidin-1-yl]urea 3.3 nM (1.0)  68

(2S)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}- N-(2-oxopropyl)-3-phenylpropanamide 12.4 nM (0.94)  69

1-(4-bromo-2-fluorophenyl)-3- [4-ethyl-2,5-dioxo-4-(2-phenylethyl)imidazolidin-1- yl]urea 13.4 nM (0.91)  70

(2S)-2-{[(4- bromophenyl)carbamoyl]amino} pentanoic acid 7.1 nM (1.0) 71

(2S)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}-N-(2-hydroxyethyl)-3- phenylpropanamide 15.6 nM (0.98)  72

methyl {[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate 16.4 nM (0.86)  73

propan-2-yl {[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}pentanoyl]amino}acetate 14.5 nM (1.0)  74

{[(2S)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}pentanoyl]amino}acetic acid 4.1 nM (0.91)  75

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- N-(2-hydroxyethyl)-4-methylpentanamide 13.5 nM (0.76)  76

1-(4-bromophenyl)-3-{4-[2- (furan-2-yl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea 5.2 nM (0.99)  77

(2S)-N-(2-amino-2-oxoethyl)-2- {[(4- bromophenyl)carbamoyl]amino}-4-methylpentanamide 1.1 nM (1.0)  78

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- 4-methyl-N-(2-oxopropyl)pentanamide 4.7 nM (0.82)  79

(2S)-N-(2-amino-2-oxoethyl)-2- {[(4- bromophenyl)carbamoyl]amino}pentanamide 2.5 nM (0.97)  80

1-(4-bromophenyl)-3-{4-[2-(2- fluorophenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea 14.3 nM (99)  81

(2S)-N-(2-amino-2-oxoethyl)-2- {[(4-bromo-2-fluorophenyl)carbamoyl]amino} pentanamide 5.2 nM (0.96)  82

1-(4-bromophenyl)-3-{4-[2-(4- fluorophenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea 16.3 nM (1.0)  83

1-(4-bromophenyl)-3-{4-[2-(3- fluorophenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea 11.1 nM (1.0)  84

(2S)-N-(2-amino-2-oxoethyl)-2- {[(4-bromo-2-fluorophenyl)carbamoyl]amino}- 4-methylpentanamide 4.5 nM (0.95)  85

(2S)-2-{[{4-bromo-2- fluorophenyl)carbamoyl]amino}- 4-methyl-N-(2-oxopropyl)pentanamide 20 nM (0.99)  86

1-(4-bromophenyl)-3-(4-[2-(4- hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea 13.3 nM (1.0)  87

(2S)-2-{[(2S)-2-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}- 4-methylpentanoyl]amino} propanoic acid 12.1 nM (0.95)  88

1-(4-bromophenyl)-3-{4- methyl-2,5-dioxo-4-[2- (thiophen-2-yl)ethyl]imidazolidin-1-yl}urea 7.9 nM (0.94)  89

1-(4-bromo-2-fluorophenyl)-3- {4-[2-(4-hydroxyphenyl)ethyl]-4-methyl-2,5- dioxoimidazolidin-1-yl}urea 8.7 nM (0.85)  90

(2S)-2-{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino} propanoic acid 11.6 nM (1.0)  91

(2S)-2-{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino}-3- methylbutanoic acid 1.7 nM (0.97)  92

(2S)-N-[(2S)-1-amino-3-methyl- 1-oxobutan-2-yl]-2-{[(4-bromophenyl)carbamoyl]amino}- methylpentanamide 5.8 nM (1.0)  93

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- N-(2-hydroxy-2-methylpropyl)-4- methylpentanamide 2.5 nM (0.93)  94

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- N-(1,3-dihydroxypropan-2-yl)-4-methylpentanamide 7.4 nM (0.96)  95

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- N-(2,3-dihydroxypropyl)-4-methylpentanamide 5.1 nM (0.98)  96

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- N-[(2R)-1-hydroxypropan-2-yl]-4-methylpentanamide 3.0 nM (1.0)  97

1-(4-bromophenyl)-3-{4- methyl-4-[2-(5-methylfuran-2-yl)ethyl]-2,5-dioxoimidazolidin- 1-yl}urea 3.5 nM (0.95)  98

1-(4-bromo-2-fluorophenyl)-3- {4-[2-(3-fluoro-4-hydroxyphenyl)ethyl]-4-methyl- 2,5-dioxoimidazolidin-1-yl}urea 7.4 nM(0.91)  99

1-(4-bromophenyl)-3-{4-[2-(3- fluoro-4-hydroxyphenyl)ethyl]-4-methyl-2,5- dioxoimidazolidin-1-yl}urea 8.0 nM (1.0) 100

tert-butyl (2S)-2-{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino} pentanoate 13.0 nM (1.0) 101

(2S)-2-{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino} pentanoic acid 1.0 nM (0.95) 102

(2S)-N-[(2S)-1-amino-1- oxopentan-2-yl]-2-{[(4-bromophenyl)carbamoyl]amino}- 4-methylpentanamide 7.3 nM (0.99) 103

(2S)-{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino} (phenyl)ethanoic acid 9.1 nM (1.0) 104

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- 4-methyl-N-(1H-tetrazol-5-ylmethyl)pentanamide 2.3 nM (0.81) 105

ethyl hydrogen ({[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino} methyl)phosphonate 0.95 nM (0.88) 106

1-(4-bromo-2-fluorophenyl)-3- {4-[2-(2-hydroxyphenyl)ethyl]-4-methyl-2,5- dioxoimidazolidin-1-yl}urea 4.0 nM (0.91) 107

1-(4-bromo-2-fIuorophenyl)-3- {4-[2-(3-hydroxyphenyl)ethyl]-4-methyl-2,5- dioxoimidazolidin-1-yl}urea 2.2 nM (0.79) 108

1-(4-bromophenyl)-3-{4-[2-(3- hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea 2.1 nM (1.0) 109

1-(4-bromophenyl)-3-{4-[2-(2- hydroxyphenyl)ethyl]-4-methyl-2,5-dioxoimidazolidin-1-yl}urea 0.97 nM (0.93) 110

2-{[(4- bromophenyl)carbamoyl]amino}- 2,4-dimethylpentanoic acid 19.4 nM(0.98) 111

[(2-{[(4- bromophenyl)carbamoyl]amino}- 2,4-dimethylpentanoyl)amino]acetic acid 19.1 nM (0.99) 112

diethyl ({[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino} methyl)phosphonate 0.48 nM (0.95) 113

(2-{[(4- bromophenyl)carbamoyl]amino}- 2-ethylbutanoyl)amino]acetic acid18.7 nM (1.0) 114

diethyl ({[(2S,3S)-2-{[(4- bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino} methyl)phosphonate 2.9 nM (1.0) 115

ethyl hydrogen ({[(2S,3S)-2- {[(4- bromophenyl)carbamoyl]amino}-3-methylpentanoyl]amino} methyl)phosphonate 2.7 nM (0.88) 116

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- N-[(3-hydroxy-1,2-oxazol-5-yl)methyl]-4- methylpentanamide 12.0 nM (1.0) 117

diethyl ({[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}pentanoyl]amino}methyl) phosphonate 0.27 nM (1.0) 118

diethyl ({[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-3-phenylpropanoyl]amino} methyl)phosphonate 16.1 nM (0.93) 119

diethyl (2-{[(2S)-2-{[(4- bromophenyl)carbamoyl] amino}-4-methylpentanoyl]amino}ethyl) phosphonate 16.1 nM (0.97) 120

(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- N-[2-(dimethylamino)-2-oxoethyl]-4-methylpentanamide 1.7 nM (0.99) 121

(2S)-2-{[(4- iodophenyl)carbamoyl]amino}- 4-methylpentanoic acid 4.0 nM(0.93) 122

(2R,3R)-2-{[(4- bromophenyl)carbamoyl] amino}-3-methylpentanoic acid 10□M (0.59) 123

ethyl hydrogen ({[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}pentanoyl]amino}methyl) phosphonate 1 nM (0.96) 124

{[(2S)-4-methyl-2-({[4- (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl] amino}acetic acid 1.8 nM (1.0) 125

dipropan-2-yl ({[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}pentanoyl]amino}methyl) phosphonate 1.2 nM (1.0) 126

ethyl hydrogen ({[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-3-phenylpropanoyl]amino} methyl)phosphonate 16.0 nM (1.0) 127

{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- 4-methylpentanoyl]amino}methanesulfonic acid 2.0 nM (0.91) 128

(2S)-4-methyl-2-({[4- (methylsulfanyl)phenyl] carbamoyl}amino)pentanoicacid 16.8 nM (0.92) 129

propan-2-yl hydrogen {[(2-{[(4- bromophenyl)carbamoyl]amino}pentanoyl)amino]methyl} phosphonate 1.87 nM (0.89) 130

{[(2S)-4-methyl-2-({[4- (methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl] amino}acetic acid 3.0 nM (1.0) 131

dipropan-2-yl ({[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl]amino} methyl)phosphonate 4.0 nM (1.0) 132

1-(4-bromophenyl)-3-[4- (hydroxymethyl)-2,5-dioxo-4-(propan-2-yl)imidazolidin-1- yl]urea 16.2 nM (0.86) 133

2-[1-{[(4- bromophenyl)carbamoyl]amino}- 2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]-N-(2- hydroxyethyl)acetamide 2.7 nM (1.0) 134

diethyl ({[(2S)-4-methyl-2-({[4- (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl] amino}methyl)phosphonate 5.5 nM (0.97) 135

ethyl hydrogen ({[(2S)-4- methyl-2-({[4- (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl] amino}methyl)phosphonate 1.9 nM (0.91) 136

(2S)-4-methyl-N-(1H-tetrazol-5- ylmethyl)-2-({[4-(trifluoromethyl)phenyl] carbamoyl}amino)pentanamide 3.7 nM (0.96) 137

{[(2S)-4-methyl-2-({[4- (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl] amino}methanesulfonic acid 1.9 nM (0.99) 138

diethyl ({[(2S)-4-methyl-2-({[4- (methylsulfanyl)phenyl]carbamoyl}amino)pentanoyl] amino}methyl)phosphonate 3.5 nM (0.91) 139

2-methyl-2-{[(2S)-4-methyl-2- ({[4- (trifluoromethyl)phenyl]carbamoyl}amino)pentanoyl] amino}propanoic acid 2.5 nM (0.92) 140

tert-butyl (2S)-2-{[(4- bromophenyl)sulfamoyl] amino}-4-methylpentanoateNA 141

methyl 2-[2-(1-{[(4- bromophenyl)carbamoyl] amino}-4-ethyl-2,5-dioxoimidazolidin-4- yl)ethyl]benzoate 10.3 nM (0.92) 142

2-[1-{[(4- bromophenyl)carbamoyl] amino}-2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]-N-(1,3- dihydroxypropan-2- yl)acetamide 13.8 nM(0.92) 143

2-[2-(1-{[(4- bromophenyl)carbamoyl] amino}-4-ethyl-2,5-dioxoimidazolidin-4- yl)ethyl]benzoic acid 17.2 nM (1.0) 144

{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- 4-(methylsulfanyl)butanoyl]amino}acetic acid 6.3 nM (0.91) 145

3-({[1-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2- yl)imidazolidin-4- yl]acetyl}amino)propanoic acid1.0 nM (1.0) 146

2-[2-(1-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}-4-ethyl-2,5-dioxoimidazolidin- 4-yl)ethyl]benzoic acid 11.1 nM (1.0) 147

3-({[1-{[(4- bromophenyl)carbamoyl]amino}- 2,5-dioxo-4-(propan-2-yl)imidazolidin-4- yl]acetyl}amino)propanoic acid 3.9 nM (0.99) 148

2-[1-{[(4-bromo-2- fluorophenyl)carbamoyl]amino}- 2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]-N-(2- hydroxyethyl)acetamide 6.9 nM (0.98) 149

ethyl 3-[1-{[(4- bromopheml)carbamoyl]amino}- 2,5-dioxo-4-(propan-2-yl)imidazolidin-4-yl]propanoate 6.6 nM (0.94) 150

{[2-{[(4- bromophenyl)carbamoyl] amino}-3-(1H-indol-3-yl)propanoyl]amino}acetic acid 1.4 nM (0.98) 151

2-{2-[1-{[(4- bromophenyl)carbamoyl]amino}- 2,5-dioxo-4-(propan-2-yl)imidazolidin-4- yl]ethyl}benzoic acid 5.8 nM (1.0) 152

diethyl [2-({[1-{[(4- bromophenyl)carbamoyl]amino}-2,5-dioxo-4-(propan-2- yl)imidazolidin-4- yl]acetyl}amino)ethyl]phosphonate 11 nM (1.0) 153

ethyl 3-{[(4- bromophenyl)carbamoyl]amino}- 2,4-dioxo-1,3-diazaspiro[4.5]decane-8- carboxylate 12 nM (0.99) 154

tert-butyl {[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}-4-methylpentanoyl](methyl) amino}acetate 12 nM (0.85) 155

{[(2S)-2-{[(4- bromophenyl)carbamoyl]amino}- 4-methylpentanoyl](methyl)amino}acetic acid 1.0 nM (1.0)

Immunohistochemistry: Fluorescent immunohistochemistry with antibodiesspecific to FPR2 was used to determine localization in normal humanskin. Anti-FPR2 antibody (Abcam) was used at a dilution of 1:200 todetect FPR2 protein.

Dermal wound healing model: Groups of 5 ICR male mice weighing 24-28 gwere used.

During the study, the tested animals were housed in individual cages.Under hexobarbital (90 mg/kg, i.p.) anesthesia, the shoulder and backregion of each animal was shaved. A sharp punch (ID 12 mm) was appliedto remove the skin including panniculus carnosus and adherent tissues.The wound area, traced onto clear plastic sheets, was measured by use ofan Image—ProPlus (Media Cybernetics, Version 4.5.0.29) on days 1, 3, 5,7, 9 and 11. Test substances and vehicle (Placebo, 20 μL/mouse) wereadministered topically (TOP) once daily post skin punch for a total of10 consecutive days. The positive control of CGS-21680 in 0.5% CMC/PBS,pH 7.4 was given topically as the same regimen. The percent closure ofthe wound (%) was calculated, and wound half-closure time (CT50) wasanalyzed by linear regression using Graph-Prism (Graph Software USA).One-way ANOVA followed by Dunnett's test was applied for comparisonbetween the treated and vehicle groups at each measurement time point.Differences are considered significant at P<0.05.

LL37-induced model of rosacea in mice: Prior to dosing, animals arelightly anaesthetized with isofluorane and baseline right and left earthickness measurements are made with a digital caliper (Mitutoyo293-340). At t=−1 hrs, animals are lightly anaesthetized with isofluraneto allow topical application (dorsal side) of 10 μL of FPR2 agonistformulated in a vehicle consisting of PBS:ethanol (50:50), or vehiclecontrol to both ears. At t=0 hr, mice are re-anaesthetized. Followingear thickness measurements, 20 uL of LL-37 (100 μM) is injected into theright ear, while PBS is injected into the left ear. Additional earthickness measurements are taken at t=3 and 6 hours. After the last timepoint, mice are euthanized by CO₂ inhalation and ears collected foradditional analyses.

In vitro human skin penetration model: Briefly, split-thickness humanabdominal skin (˜0.50 mm) sections from two donors were mounted inflow-through diffusion cells (PermeGear). FPR2 agonists are applied at adose of 10 μL to a surface area of 0.64 cm² (n=7 per compound). PBS ispumped beneath the skin at a constant flow rate of ˜42 μL/min. Receptorfluid samples are collected at 1, 3, 6, 12, and 24 hrs and analyzed byLC/MS/MS.

What is claimed is:
 1. A method of treating dermal inflammation or adermal disease in a subject in need of such treatment, the methodcomprising administering to the subject a pharmaceutical compositioncomprising a therapeutically effective amount of a formyl peptidereceptor 2 (FPR2) agonist of Formula I:

wherein: R¹ is sec-butyl, C₆₋₁₀ aryl, —CH₂— (C₆₋₁₀)aryl,—CH₂-heterocycle, C₄₋₈ cycloalkyl or C₃₋₈ cycloalkenyl or heterocycle;R² is halogen or methyl; R³ is halogen; R⁴ is H, methyl or halogen; R⁵is OR⁶ or NH₂; and R⁶ is H or C₂₋₄ alkyl; or a pharmaceuticallyacceptable salt thereof; or wherein the FPR2 agonist is a compoundselected from the group consisting of:

and pharmaceutically acceptable salts thereof; and wherein the dermalinflammation or dermal disease is selected from the group consisting ofdermal wound healing, hypertrophic scars, keloids, burns, rosacea,atopic dermatitis, acne, psoriasis, seborrheic dermatitis, actinickeratoses, basal cell carcinoma, squamous cell carcinoma, melanoma,viral warts, photoaging, photodamage, melasma, post-inflammatoryhyperpigmentation, disorders of pigmentation and alopecia, scarring andnon-scarring forms; and wherein the administration is by local delivery.2. The method of claim 1, wherein the compound of Formula I is:

or a pharmaceutically acceptable salt thereof.
 3. The method of claim 1,wherein the compound is

or a pharmaceutically acceptable salt thereof.
 4. The method of claim 1,wherein the local delivery is topical dermal delivery.
 5. The method ofclaim 2, wherein the local delivery is topical dermal delivery.
 6. Themethod of claim 3, wherein the local delivery is topical dermaldelivery.
 7. The method of claim 4, wherein the pharmaceuticalcomposition is in a form selected from the group consisting of a cream,a lotion, a gel, a solution, a spray, a foam, a suspension and anemulsion.
 8. The method of claim 5, wherein the pharmaceuticalcomposition is in a form selected from the group consisting of a cream,a lotion, a gel, a solution, a spray, a foam, a suspension and anemulsion.
 9. The method of claim 6, wherein the pharmaceuticalcomposition is in a form selected from the group consisting of a cream,a lotion, a gel, a solution, a spray, a foam, a suspension and anemulsion.